Proprotein convertase subtilisin/kexin type 4 in mammalian fertility: a review

Proprotein convertase subtilisin/kexin type 4 (PCSK4), also known as proprotein convertase 4, belongs to a family of endoproteinases involved in the proteolytic conversion of secretory precursor proteins to their active forms. Its amino acid sequence is highly conserved in mammals, an indication of its biological importance. We have searched PubMed and molecular biology databases for information relating to the structure, expression and biological functions of PCSK4. PCSK4 is predominantly expressed in male germ cells and located on the plasma membrane overlying the acrosome of sperm. It is also present in ovary and placenta. Inactivation of its gene in mouse does not alter spermatogenesis, but renders sperm incapable of fertilizing oocytes. This incapacity results in part from sperm susceptibility to a premature acrosome reaction and their reduced ability to bind to the zona pellucida. In female mice, a lack of PCSK4 causes subfertility associated with impaired folliculogenesis. In addition, this enzyme has been shown to stimulate the invasiveness of human placental trophoblasts in culture, suggesting that it may facilitate placentation in vivo. PCSK4 appears to be a crucial enzyme for reproduction. Alterations of PCSK4 expression or activity could be the underlying cause of some unexplained cases of human infertility. Conversely, inactivation of this protease represents a potential strategy for non-hormonal contraception.